Hollow fiber membrane for purifying blood

ABSTRACT

It is intended to provide a blood purification membrane having excellent performance and showing little elution of blood and little adhesion of blood proteins or platelets. The above object can be achieved by using a moisten membrane, which is free from any membrane pore-sustaining agent and has a high water permeation dose and a large pore size, and lessening the pore size by drying the membrane after desolvation.

TECHNICAL FIELD

[0001] The present invention relates to a high performance bloodpurification membrane having excellent dialysis performance and allowinglittle elution from the membrane and little adhesion of blood proteinsand platelets and to a method for manufacturing the membrane.

BACKGROUND ART

[0002] Progress of the technology utilizing membranes having selectivepermeability has been remarkable in recent years. Such membranes areused in practice in an extensive field as a gas-liquid separation filterand as hemodialysis equipment, blood filter equipment, and a filter forselective separation of blood components in the medical field.

[0003] As materials for the membrane, polymers such as cellulose(regenerated cellulose, cellulose acetate, chemically modifiedcellulose, etc.), polyacrylonitrile, polymethylmethacrylate,polysulfone, polyethylene vinyl alcohol, polyamide, and the like havebeen used.

[0004] Of these polymers, polysulfone-based polymers have attractedattention as materials for semipermeable membranes due to theircharacteristics of improving hemocompatibility if the membranes areproduced from a raw material polymer solution comprising ahydrophilicity promoter, in addition to the excellent heat stability,acid resistance, and alkali resistance.

[0005] Membranes must be dried to fabricate a module by causing themembranes to adhere. Porous membranes made from an organic polymer,particularly dialysis membranes and ultrafilter membranes made from ahydrophobic polymer such as polysulfone-based polymer and the like, areknown to exhibit significantly reduced water permeability when driedafter preparation as opposed to before drying. For this reason, themembranes must always be handled under wet conditions or under theconditions in which the membranes are dipped in water.

[0006] The countermeasure that has conventionally been adopted is amethod of filling vacant pores in prepared porous membranes with alow-volatile organic liquid such as glycerol before drying. However,since a low-volatile organic liquid is generally highly viscous,removing such an organic liquid by washing the membrane istime-consuming. After washing modules formed from the membrane, elutedsubstances originating from the low-volatile organic liquid (variousderivatives produced by chemical reactions with the low-volatile organicliquid) were existed in a module enclosure solution.

[0007] As a method for drying without using a low-volatile organicliquid, JP-A-6-277470 discloses a method of using an inorganic salt,such as calcium chloride and the like, instead of the low-volatileorganic liquid. However, the method still requires washing to remove theinorganic salt. Anxiety remains about an adverse effect that theremaining inorganic salt, even in a very small quantity, may have ondialysis patients.

[0008] JP-A-8-52331 and JP-B-8-9668 disclose hydrophilic membranescontaining polyvinyl pyrrolidone dried without using a low-volatileorganic liquid. The patent specifications describe performance of themembranes for separating plasma components from blood. Permeability ofplasma proteins, however, indicates that the membranes do not exhibitdialysis performance. In addition, since the patent specifications donot describe the membrane forming conditions, a third party cannotreproduce the membranes by experiments. The membrane structure itself isalso not clear. In addition, the membranes are heated in the drying stepat a temperature causing decomposition or denaturation of polyvinylpyrrolidone. The method is thus extremely undesirable from the viewpointof decreasing elution from the membranes.

[0009] JP-A-6-296686 discloses a hollow fiber membrane of which theinner surface of the membrane directly coming into contact with bloodhas a polyvinyl pyrrolidone content of about 20-50%. This hollow fibermembrane is mainly to provide a wet membrane to which blood proteins,platelets, and the like adhere in a reduced amount. Therefore, alow-volatile organic liquid such as glycerol must be adhered to preventa decrease in performance due to drying. The module manufactured fromthe resultant membrane still contains components that allow elution. Inaddition, the patent specification does not disclose at all the dialysisperformance such as low albumin permeability.

[0010] Furthermore, JP-A-2000-300663 and JP-A-2001-205057 disclosemethods for manufacturing hollow fibers without using a membrane poreholding agent. The patent specifications do not describe dialysisperformance of the resulting membranes. The technological correlationbetween the manufacturing methods and the characteristics of resultantdry membranes is not clear in these patent specifications.

DISCLOSURE OF THE INVENTION

[0011] As discussed above, neither a dry blood purification membraneexhibiting desired dialysis performance prepared without using amembrane pore holding agent that causes elution from a module nor amethod for producing such a membrane has been provided heretofore. Thereason has been that if the membrane is dried without using a membranepore holding agent, the membrane can exhibit only very low performance,which is quite different from the performance exhibited under wetconditions. Specifically, the membrane pore holding agent preventsdecrease in the membrane performance due to drying. Since the membraneperformance decreases to the extent that almost no water permeabilitycan be obtained if the membrane pore holding agent is not used, dryingwithout using the membrane pore holding agent has been inconceivable ina method of manufacturing a membrane having dialysis performance. Basedon an idea of previously preparing a wet membrane with specificperformance, having higher water permeability and larger pore size thanthe targeted performance, and producing the target membrane by dryingand constricting this previously prepared membrane, that had never beenthought of by anyone heretofore, the inventors of the present inventionconducted extensive studies. As a result, the present inventors weresuccessful in obtaining a membrane exhibiting excellent selectivepermeability and having excellent dialysis performance, and allowinglittle elution from the membrane and little adhesion of blood proteinsand platelets.

[0012] Therefore, an object of the present invention is to provide ahigh performance blood purification membrane having excellent dialysisperformance and allowing little elution from the membrane and littleadhesion of blood proteins and platelets.

[0013] A further object of the present invention is to provide a methodof preparing such a blood purification membrane.

[0014] The above and other objects, features, and advantages of thepresent invention will become apparent from the following detaileddescription and the appended claims.

[0015] According to the present invention, a hollow fiber bloodpurification membrane allowing little elution can be obtained bypreviously preparing a wet membrane having high water permeability andlarge pore size that does not contain a membrane pore holding agent, andby constricting the pore size by drying the wet membrane after removinga solvent.

[0016] The basic features and various preferred embodiment of thepresent invention will now be given for assisting better understandingof the present invention.

[0017] 1. A hollow fiber blood purification membrane allowing littleelution, which is a dry membrane containing no membrane pore holdingagent, obtained by previously preparing a wet membrane containing nomembrane pore holding agent and having high water permeability and largepore size and constricting the pore size by drying the wet membraneafter removing a solvent.

[0018] 2. The hollow fiber blood purification membrane described in 1above, which is a dry membrane containing no membrane pore holding agentprepared by providing a wet membrane made from a material comprisingpolysulfone-based polymer and polyvinyl pyrrolidone, which does notcontain a membrane pore holding agent and has a pure water permeabilityof not less than 100 mL/(m²·hr·mmHg), permeability of polyvinylpyrrolidone with a weight average molecular weight of 40,000 of morethan 75%, and permeability of albumin in bovine blood plasma of not lessthan 0.3%, and drying the wet membrane at a temperature of not more than120° C., the dry membrane:

[0019] (a) having a sponge-like structure with the pore sizecontinuously decreasing from the outer surface of the membrane towardthe compact layer of the inner surface,

[0020] (b) having pure water permeability of 10-1,000 mL/(m²·hr·mmHg),

[0021] (c) having polyvinyl pyrrolidone (weight average molecular weightof 40,000) permeability of not more than 75%,

[0022] (d) having permeability of albumin in bovine blood plasma of lessthan 0.3%,

[0023] (e) having an absorbance in a membrane elution test solution ofless than 0.04 and not containing a membrane pore holding agent in theelution test solution, and

[0024] (f) comprising a polysulfone-based polymer and polyvinylpyrrolidone, with a polyvinyl pyrrolidone content of 30-45 wt % on theinner surface of the membrane.

[0025] 3. The blood purification membrane described in 1 or 2 above,containing polyvinyl pyrrolidone insoluble in water.

[0026] 4. A method for preparing a hollow fiber blood purificationmembrane allowing little elution, which is a dry membrane containing nomembrane pore holding agent, the method comprising previously preparinga wet membrane containing no membrane pore holding agent and having highwater permeability and large pore size and constricting the pore size bydrying the wet membrane after removing a solvent.

[0027] 5. The method for preparing the hollow fiber blood purificationmembrane described in 4 above, wherein the method comprises providing awet membrane made from a material comprising polysulfone-based polymerand polyvinyl pyrrolidone, which does not contain a membrane poreholding agent and has a pure water permeability of 100 mL/(m²·hr·mmHg),permeability of polyvinyl pyrrolidone with a weight average molecularweight of 40,000 of more than 75%, and permeability of albumin in bovineblood plasma of not less than 0.3%, and drying the wet membrane at atemperature of not more than 120° C., and the dry membrane:

[0028] (a) having a sponge-like structure with the pore sizecontinuously decreasing from the outer surface of the membrane towardthe compact layer of the inner surface,

[0029] (b) having a pure water permeability of 10-1,000 mL/(m²·hr·mmHg),

[0030] (c) having a polyvinyl pyrrolidone (weight average molecularweight of 40,000) permeability of not less than 75%,

[0031] (d) having permeability of albumin in bovine blood plasma of lessthan 0.3%,

[0032] (e) having an absorbance in a membrane elution test solution ofless than 0.04 and not containing a membrane pore holding agent in theelution test solution, and

[0033] (f) comprising polysulfone-based polymer and polyvinylpyrrolidone, with a polyvinyl pyrrolidone content of 30-45 wt % on theinner surface of the membrane,

[0034] the method comprising providing a wet membrane made from amaterial comprising polysulfone-based polymer and polyvinyl pyrrolidone,which does not contain a membrane pore holding agent and has a purewater permeability of 100 mL/(m² hr mmHg), permeability of polyvinylpyrrolidone with a weight average molecular weight of 40,000 of morethan 75%, and permeability of albumin in bovine blood plasma of 0.3% ormore, and drying the wet membrane at a temperature of 120° C. or less.

[0035] 6. The method for preparing the wet membrane described in 4 or 5above, comprising injecting a raw material polymer solution and an innerliquid from double-ring nozzles, causing the injected material to passthrough an air gap, and causing the material to coagulate in acoagulation bath, thereby producing a hollow fiber membrane, wherein theratio of the air gap to the spinning speed is 0.01-0.1 m/(m/min).

[0036] 7. The method described in 6 above, wherein the raw materialpolymer solution comprises polysulfone-based polymer, polyvinylpyrrolidone and solvent, with the ratio of polyvinyl pyrrolidone to thepolysulfone-based polymer being 18-27 wt %.

[0037] 8. The method described in 4-7 above, wherein the membrane isirradiated with radiation after drying.

[0038] The hollow fiber blood purification membrane (hereinafter mayreferred to simply as “membrane” or “hollow fiber membrane” from time totime) of the present invention will now be described.

[0039] The membrane of the present invention is a dry membrane notcontaining a membrane pore holding agent, does not possess a polymerdeficient part where the pore size of the membrane exceeds 10 μm, andhas a sponge-like structure with the pore size continuously decreasingfrom the outer surface of the membrane toward the compact layer of theinner surface.

[0040] The hollow fiber membrane of the present invention possesses astructure that continues from one surface of the membrane to the othersurface, for example, from the inner surface to the outer surface of themembrane. The section from the outer surface of the membrane toward thecompact layer of the inner surface, that is to say, the inner section ofthe membrane, possesses a mesh structure with a mesh (pore) size of notmore than 10 μm without a polymer deficient part where the pore sizeexceeds 10 μm (large vacant pore or void) In the present invention, thisstructure is referred to as a sponge-like structure.

[0041] In the present invention, the compact layer means a layer inwhich the void areas (i.e. the pores) of the polymer forming thestructure of the membrane in the cross section in the thicknessdirection are small and which contributes to the fractionatingperformance of the membrane.

[0042] The pores of the mesh network of the inner section of themembrane have an inclined structure in which the pore size continuouslydecreases from the outer surface of the membrane toward the compactlayer of the inner surface in the cross section perpendicular to thelength direction of the membrane. Specifically, in the case of severalconcentric cylindrical surfaces, all having the same central axisextending in the length direction of the hollow fiber membrane, theaverage pore size in each of these surfaces continuously decreases fromthe outer surface of the membrane toward the compact layer of the innersurface. When blood comes into contact with the inner surface side ofthe membrane, if the membrane does not have a structure which the poresize continuously decreases from the outer surface of the membranetoward the compact layer of the inner surface, a sharp fractionatingperformance cannot be achieved.

[0043] The membrane pore holding agent referred to in the presentinvention is a substance that is filled in the vacant pores of themembrane during the production process up until a drying step to preventdecrease in the performance of the membrane during drying. It ispossible to fill the vacant pores of the membrane with the membrane poreholding agent by dipping a wet membrane into a solution comprising themembrane pore holding agent. If the membrane pore holding agent iswashed and removed after drying, the membrane can possess theperformance equivalent to a wet membrane such as water permeability andrejection rate due to the effect of the membrane pore holding agent.There have been reports that a small amount of the membrane pore holdingagent remaining in the membrane and/or the module enclosure solutionchemically reacts with the membrane pore holding agent to producevarious kinds of derivatives, and these derivatives remain in themembrane. However, since the membrane pore holding agent is not used inthe membrane during the production process in the present invention,there are no eluted substances resulting from the membrane pore holdingagent.

[0044] An absorbance of elution test solution of the membrane of thepresent invention is less than 0.04, and the test solution does notcontain a membrane pore holding agent. Here, the elution test solutionis prepared according to the hemodialysis apparatus approval standard,which comprises placing 1.5 g of dry hollow fiber membrane cut intopieces with a length of 2 cm and 150 mL of distilled water for injectionin a glass container conforming to the alkali elution test for theinjection glass container examination according to the JapanesePharmacopoeia, heating the mixture at 70±5° C. for one hour, removingthe membrane, and adding distilled water to make the total volume 150mL. The absorbance is measured using ultraviolet absorption spectrumexhibiting the maximum absorption wavelength at 220-350 nm Thehemodialysis apparatus approval standard requires an absorbance of 0.1or less, whereas the membrane of the present invention can achieved anabsorbance of less than 0.04 due to using no membrane pore holdingagent. The absence or presence of the membrane pore holding agent can bedetected by analyzing the sample obtained by condensing the testsolution or removing water from the test solution using a known method,such as gas chromatography, liquid chromatography, differentialrefractometer, ultraviolet spectrophotometer, an infraredabsorptiometric method, a nuclear magnetic resonance spectroscopicmethod, or elemental analysis.

[0045] As examples of the membrane pore holding agent, glycol orglycerol compounds, such as ethylene glycol, propylene glycol,trimethylene glycol, 1,2-butylene glycol, 1,3-butylene glycol,2-butyne-1,4-diol, 2-methyl-2,4-pentadiol, 2-ethyl-1,3-hexanediol,glycerol, tetraethylyne glycol, polyethylene glycol 200, polyethyleneglycol 300, and polyethylene glycol 400; organic compounds, such assucrose fatty acid ester; and inorganic salts, such as calcium chloride,sodium carbonate and sodium acetate can generally be given.

[0046] The membrane of the present invention comprises apolysulfone-based polymer and polyvinyl pyrrolidone, with a polyvinylpyrrolidone content of 30-45 wt % on the inner surface of the membrane.The hydrophilicity of the inner surface of the membrane with which theblood comes into contact is a key factor in the hemocompatibility of themembrane. When the membrane is a polysulfone-based membrane comprisingpolyvinyl pyrrolidone (hereinafter abbreviated as “PVP”), the PVPconcentration of the inner surface of the membrane is important. If thePVP concentration of the inner surface of the membrane is too low, theinner surface of the membrane exhibits hydrophobic, becomes easy toabsorb plasma protein, and the blood is prone to clotting. Thehemocompatibility of the membrane becomes poor. On the other hand, ifthe PVP concentration is too high, the eluted amount of the PVP in theblood increases and has an unfavorable effect on the objective and useof the present invention. Therefore, the PVP concentration of the innersurface of the membrane of the present invention is usually 30-45%, with33-40% being preferable.

[0047] As the polysulfone-based polymer used in the present invention,polysulfone-based polymers possessing the repeating units shown by thefollowing formulas (1) or (2) can be given. In the formulas, Arrepresents a di-substituted (para-position) phenyl group, with noparticular limitation to the degree of polymerization and molecularweight.

—O—Ar—C(CH₃)₂—Ar—O—Ar—SO₂—Ar—  (1)

—O—Ar—SO₂—Ar—  (2)

[0048] The PVP concentration of the inner surface of the membrane isdetermined by X-ray photoelectron spectroscopy (hereinafter abbreviatedas XPS). Specifically, the sample is placed on double-sided tape, is cutin the axial direction of the fibers and spread open to expose theinside of the membrane, then XPS measurement is conducted using anordinary method. The PVP concentration is determined from the nitrogenconcentration (nitrogen atom concentration) on the surface and thesulfur concentration (sulfur atom concentration) on the surface and fromthe area strength of Cls, Ols, Nls, and S2p spectra using a relativesensitivity coefficient appended to the apparatus. When thepolysulfone-based polymer has the formula (1), the PVP concentration canbe calculated from the following formula (3). $\begin{matrix}{{{PVP}\quad {concentration}\quad ( {{wt}\quad \%} )} = {\frac{C_{1}M_{1}}{{C_{1}M_{1}} + {C_{2}M_{2}}} \times 100}} & (3)\end{matrix}$

[0049] wherein C₁: Nitrogen atom concentration (%)

[0050] C₂: Sulfur atom concentration (%)

[0051] M₁: Molecular weight of the repeating units of PVP (111)

[0052] M₂: Molecular weight of the repeating units of polysulfone-basedpolymer (442)

[0053] The membrane of the present invention has a pure waterpermeability of not less than 10 mL/(m²·hr·mmHg), with not less than 15mL/(m²·hr·mmHg) being more common. An amount less than 10mL/(m²·hr·mmHg) is not preferable due to the inferior water removalcapability during dialysis. This shows that the membrane of the presentinvention possesses excellent water permeability even when dried.

[0054] In recent hemodialysis treatment methods, membranes allowingsufficient permeation of β₂-microglobulin (molecular weight: 11,800)which is known to cause dialysis amyloidosis, and possessing afractionating performance that prevents permeation of nearly all of thealbumin (molecular weight: 67,000) have been desired. The membrane ofthe present invention has a permeability of albumin in bovine bloodplasma of not more than 0.3%. If the permeability of the albumin exceeds0.3%, a great loss in effective albumins in a body occurs. Such highalbumin permeability is therefore not preferable for a hemodialysismembrane.

[0055] The permeability of albumin in bovine blood serum can be measuredusing the following method. First, 100 hollow fiber membranes 20 cm longare bundled together to form a small module. Bovine serum containingheparin (heparin amount: 5,000 IU/I, protein concentration: 6.0 g/dL(deciliters)) is heated to 37° C. and passed through the inner surfaceside of the membrane in the module at a linear speed of 1.0 cm/second tocarry out ultrafiltration for 30 minutes with the average input andoutput pressure of the module being 50 mmHg. The concentrations of theobtained filtrate and the solution before filtering are determined bymeasuring the absorbance at a wavelength of 280 nm using an ultravioletspectrophotometer. The permeability is calculated using the followingformula (4). $\begin{matrix}{{{Permeability}\quad (\%)} = {\frac{{absorbance}\quad {of}\quad {filtrate}}{\begin{matrix}{{absorbance}\quad {of}\quad {solution}} \\{{before}\quad {filtering}}\end{matrix}} \times 100}} & (4)\end{matrix}$

[0056] A linear functional correlation shown by the following formula(5) is applicable between the permeability of polyvinyl pyrrolidone(A(%)) and the clearance of β₂-microglobulin (B (mL/min)) in themembrane having a distilled water permeability of 10 mL/(m²·hr·mmHg) ormore. Usually, to evaluate the clearance, a dialysis module possessingan effective membrane surface area of 1.5 m² must be prepared. However,the clearance value can be easily speculated using the simple and easyevaluation method of the present invention.

B(mL/minute)=0.636A+29.99  (5)

[0057] Here, the β2-microglobulin clearance is measured by dialysisunder the conditions of a 200 mL/minute blood flow rate (inner surfaceside of the membrane) and a 500 mL/minute dialysis liquid flow rate(outer surface side of the membrane) in a module having an effectivearea of 1.5 m² in accordance with the standards determined by theJapanese Society for Artificial Organs.

[0058] Several factors such as the physical strength of the patient,conditions of the disease, and progress of the disease must be takeninto account for the determination of the β₂-microglobulin clearance.The permeability of polyvinyl pyrrolidone, however, must be below 75%because if the permeability of the polyvinyl pyrrolidone exceeds 75%,the permeability of albumin will exceed 0.3%.

[0059] The permeability of polyvinyl pyrrolidone can be measured in thesame manner as the permeability of albumin in bovine serum except forusing a phosphoric acid buffer (0.15 mol/liter, pH 7.4) aqueous solutioncomprising 3 wt % of polyvinyl pyrrolidone (K30, manufactured by BASF;weight average molecular weight: 40,000) as the aqueous solution forfiltration and regulating the average input and output pressure of themodule to 200 mmHg.

[0060] Examples of the method for producing the blood purificationmembrane of the present invention will now be described.

[0061] A wet membrane possessing large pores and high water permeabilitywithout containing a membrane pore holding agent is prepared beforehand.After removing the solvent, the wet membrane is dried to constrict thepore size. The pore size of the membrane is further constricted bymaking a portion of the PVP in the membrane insoluble in water. In themethod for producing the wet membrane, in which the raw material polymersolution comprising a polysulfone-based polymer (hereinafter referred tosimply as “polymer”), polyvinyl pyrrolidone, and a solvent is dischargedfrom a dual ring nozzle and caused to pass through an air gap into acoagulation bath for coagulation. The wet membrane can thus be preparedusing an aqueous solution of the polymer solvent as the inner solution.The inner solution is used for producing the hollow spaces and innersurface of the membrane. It is known that the pore size of the innersurface increases in proportion to the solvent concentration of theinner solution. Since the dialysis membrane with the target performancecan be obtained by drying and constricting the wet membrane in thepresent invention, the solvent concentration of the inner solution mustbe higher than the solvent concentration used for producing a wetmembrane possessing the target dialysis performance.

[0062] In the present invention, the wet membrane possessing highlywater permeability and a large pore diameter is one having a waterpermeability of 100 mL/(m²·hr·mmhg) or more, a polyvinyl pyrrolidone(weight average molecular weight: 40,000) permeability of more than 75%,and an albumin permeability in bovine serum of not less than 0.3%. Thehigher the molecular weight of polyvinyl pyrrolidone, the higher thehydrophilicity of the membrane produced from the polyvinyl pyrrolidone.Thus, the larger the molecular weight, a smaller is the amount of thepolyvinyl pyrrolidone required for achieving a target effect. For thisreason, polyvinyl pyrrolidone with a weight average molecular weight of900,000 or more is used. If a polyvinyl pyrrolidone having a weightaverage molecular weight of less than 900,000 is used to givehydrophilic effect to the membrane, a large amount of the polyvinylpyrrolidone must remain in the membrane thereby causing an increase inthe amount of substances eluted from the membrane. On the other hand, ifpolyvinyl pyrrolidone having a weight average molecular weight of lessthan 900,000 remaining in the membrane is reduced to decrease the amountof eluted substances in the membrane, the hydrophilic effect becomesinsufficient. This causes a decrease in the filtration rate over timeduring hemodialysis and a sufficient effect cannot be obtained.

[0063] The solvent used for dissolving the polysulfone-based polymer andpolyvinyl pyrrolidone can dissolve both of these substances, as saidsolvent N-methyl-2-pyrrolidone, N,N-dimethylformamide, and N,N-dimethylacetoamide can be given.

[0064] There are no specific limitations to the polymer concentration inthe raw material polymer solution as long as the concentration allows toproduce a membrane, and the membrane obtained has the requiredproperties. The concentration is usually 5-35 wt %, with 10-30 wt %being preferable. In order to attain high water permeability, a lowpolymer concentration is better. Therefore, a concentration of 10-25 wt% is further preferable.

[0065] The amount of polyvinyl pyrrolidone to be added is alsoimportant. The mixed ratio of the polyvinyl pyrrolidone to the polymeris usually 27 wt % or less, preferably 10-27 wt %, and particularlypreferably 20-27 wt %. If the mixed ratio of the polyvinyl pyrrolidoneto the polymer exceeds 27 wt %, the amount of eluted substances tends toincrease. If the mixed ratio is below 10 wt %, the viscosity of the rawmaterial polymer solution decreases and it is difficult to obtain amembrane with a sponge-like structure. Fourth components, such as waterand a poor solvent, may be added with an objective of controlling theviscosity and dissolution conditions of the raw solution. The type andamount of the fourth components can be appropriately selected based onthe combination thereof.

[0066] The inner solution is used for producing the hollow spaces andinner surface of the membrane. Water or an aqueous solution of the abovesolvents can be used as the inner solution.

[0067] The air gap is a space between the nozzle and the coagulationbath. The ratio of the air gap (m) to the spinning speed (m/minute) isvery important to obtain the membrane of the present invention. This isbecause the membrane structure of the present invention can be obtainedonly when the over time phase separation of the raw material polymersolution from the inner surface side to the outer surface side isinduced by the contact of non-solvent components in the inner liquidwith the raw material polymer solution, and the phase separation fromthe inner surface side to the outer surface side of the membrane iscompleted by the time when the raw material polymer solution is fed inthe coagulation bath.

[0068] The ratio of the air gap to the spinning speed is preferably0.010-0.1 m/(m/min), and more preferably 0.010-0.05 m/(m/min). If theratio of the air gap to the spinning speed is less than 0.010 m/(m/min),it is difficult to obtain a membrane possessing the structure andperformance of the present invention. If the ratio is more than 0.1m/(m/min), the tension to the membrane increases so that the membranemay be frequently cut at the air gap point, making the productionprocess difficult.

[0069] Spinning speed herein referred to indicates a winding speed ofthe membrane wound without being stretched during a series of hollowfiber membrane manufacturing operations, in which the raw materialpolymer solution is injected from nozzles together with the innerliquid, the spun membrane is caused to pass through the air gap andcoagulated in the coagulation bath, and the coagulated membrane is woundaround a reel. The hollow fiber membrane can be manufactured in a morestable manner by surrounding the air gap using a cylinder or the likeand causing gas having a specific temperature and humidity to flow inthe air gap at a specific flow rate.

[0070] As the coagulation bath, a liquid not dissolving the polymerincluding, for example, water; alcohols such as methanol and ethanol;ethers; and aliphatic hydrocarbons such as n-hexane and n-heptane, canbe used. Of these, water is preferable. It is possible to control thecoagulation speed by adding a slight amount of a solvent in which thepolymer is soluble to the coagulation bath.

[0071] The temperature of the coagulation bath is −30 to 90° C.,preferably 0 to 90° C., and still more preferably 0 to 80° C. If thetemperature of the coagulation bath is more than 90° C. or less than−30° C., the surface conditions of the hollow-fiber membrane isdifficult to be stable in the coagulation bath.

[0072] There are no specific limitations to the method of drying afterremoval of solvent and washing inasmuch as polyvinyl pyrrolidone is notdenatured or decomposed. The drying temperature is preferably 120° C. orless, and still more preferably 100° C. or less. If more than 120° C.,polyvinyl pyrrolidone may be denatured or decomposed, unpreferably,resulting in an increase in the amount of elution from the dry membraneproduced without using a membrane pore holding agent.

[0073] Elution from the membrane can be reduced, since a part of PVP inthe membrane can be insolubilized in water by irradiating the drymembrane with radiation such as electron beams and the γ-rays.Irradiation may be performed either before or after preparation of themodule. In spite of the reduction in the amount of elution,insolubilizing all the amount of PVP in the membrane is undesirablebecause the leukopenia symptom is observed during dialysis.

[0074] PVP insoluble in water in the present invention indicates theamount remaining after subtracting the amount of water-soluble PVP fromthe total amount of PVP in the membrane. The total amount of PVP in themembrane can be easily calculated by elementary analysis of nitrogen andsulfur. The amount of water-soluble PVP can be determined using thefollowing method.

[0075] The amount water-soluble PVP can be determined by completelydissolving the membrane in N-methyl-2-pyrrolidone, adding water to theresulting polymer solution to cause polysulfone polymer to completelyprecipitate, allowing the polymer solution to stand still, andquantitatively determining the amount of PVP in the supernatant liquidusing a liquid chromatography.

BEST MODE FOR CARRYING OUT THE INVENTION

[0076] The present invention will be described by examples, which shouldnot be construed as limiting the present invention.

[0077] (Measurement of Platelet Adhesion)

[0078] The amount of platelet adhesion to the membrane was measuredaccording to the following procedure.

[0079] Ten hollow fiber membranes measuring 15 cm in length were bundledtogether to form a small module. After causing heparin-added fresh humanblood to pass through this module at a speed of 1.0 cm/second for 15minutes, a physiological saline solution was caused to pass through themodule for 1 minute. Next, the hollow fiber membrane was cut into 5 mmpieces, placed in a physiological saline solution comprising 0.5% ofpolyethylene glycol alkylphenyl ether (Triton X-100, manufactured byWako Pure Chemical Industries, Ltd.), and subjected to ultrasonicirradiation. The lactate dehydrogenase (hereinafter referred to as“LDH”) released from the platelets adhered to the surface of themembrane was quantitatively measured to determine the amount of theadhered platelets as the LDH activity per unit area of the membrane(converted to the inner surface area). The enzyme activity was measuredusing a LDH mono test kit (manufactured by Boehringer Mannheim andYamanouchi Pharmaceutical Co., Ltd.) As a positive control, a membranenot comprising PVP (obtained by soaking the membrane of Example 1 beforeexposure to γ-ray irradiation in sodium hypochlorite having an availablechlorine concentration of 1500 ppm for 2 days and in ethanol for 1 day)was prepared and compared alongside the membrane of the presentinvention.

[0080] (Amount of Plasma Protein Absorption)

[0081] After determining the amount of adsorbed plasma proteins in thesame manner as in the determination of the albumin permeability rate,with exception of an ultrafiltration time of 240 minutes, the membranewas washed with a physiological saline solution for one minute. Next,the hollow fiber membrane was cut into 5 mm pieces and stirred in aphysiological saline solution comprising 1.0% sodium lauryl sulfate toextract plasma proteins, of which the amount was measured to determinethe protein adsorption amount per unit weight of the membrane.

[0082] The protein concentration was measured using a BCA Protein Assay(manufactured by Wako Pure Chemical Industries, Ltd. of Japan). As apositive control, a membrane not comprising PVP (obtained by soaking themembrane of Example 1 before exposure to 7-ray irradiation in sodiumhypochlorite having an available chlorine concentration of 1500 ppm for2 days and in ethanol for 1 day) was prepared and compared alongside themembrane of the present invention.

EXAMPLE 1

[0083] 18.0 wt % of polysulfone (P-1700, manufactured by AmocoEngineering Polymers of the U.S.) and 4.3 wt % of polyvinyl pyrrolidone(K90, manufactured by BASF of Germany; weight average molecular weight:1,200,000) were dissolved in 77.7 wt % of N,N-dimethyl acetoamide toform a homogenous solution. The mixture ratio of polyvinyl pyrrolidoneto polysulfone in the raw material polymer solution was 23.9 wt %. Whilemaintaining the temperature of at 60° C., this raw material polymersolution was discharged from a spinning nozzle (double-ring nozzle, 0.1mm-0.2 mm-0.3 mm) together with an inner liquid consisting of 30 wt % ofN,N-dimethyl acetoamide and 70 wt % of water. The spun membrane wascaused to pass through a 0.96 m air gap and sent to a coagulation bathof water at a temperature of 75° C. for soaking.

[0084] The path from the spinning nozzle to the coagulation bath isenclosed with a cylindrical tube. The humidity and temperature in thistube was controlled at 54.5% and 51° C., respectively, by circulatingnitrogen gas containing steam through the tube. A spinning speed wasfixed to 80 m/min. The ratio of the air gap to the spinning speed was0.012 m/(m/min).

[0085] After cutting the wound fiber, the fiber was washed for 2 hoursusing an 80° C. hot water shower splashed from the upper cut section ofthe bundle to remove the remaining solvent from the membrane. Themembrane was then dried for 7 hours using 87° C. heated wind to obtain adry membrane having a water content of less than 1%. A portion of thePVP in the membrane was insolubilized by irradiating the obtained drymembrane with γ-rays at 2.5 Mrad.

[0086] This membrane does not possess a polymer deficient part with apore size larger than 10 μm inside the membrane and has a sponge-likestructure with the pore size continuously decreasing from the outersurface of the membrane toward the compact layer of the inner surface.The thickness of the compact layer of the inner surface was about 10 μm.The performance of this membrane is shown in Table 1. Theβ₂-microglobulin clearance of a module having an effective filtrationarea of 1.5 m formed from this membrane was measured to find that themodule possessed a β₂-microglobulin clearance of 32 mL/min, almostequivalent to the clearance of 32.5 mL/min calculated by applying thePVP permeability to the formula (5). 62% of the entire PVP in themembrane was insoluble in water.

[0087] As a result of the elution test of the membrane, the membraneelution test solution was found to exhibit absorbance of 0.04 or less.Since a membrane pore holding agent was not used, no membrane poreholding agent was found in the elution test solution.

[0088] As compared with the positive control membrane, this membrane hada lower platelet adhesion amount (positive control membrane: 43.4Unit/m²) and a lower plasma protein adhesion amount (positive controlmembrane: 62.5 mg/g).

[0089] As can be clearly seen from the above performance, the membraneallows elution in only a very small amount and exhibits only a smallamount of blood protein and blood platelet adhesion. In addition, themembrane possesses low albumin permeability and excels inβ₂-microglobulin clearance. The membrane thus also excels in dialysisperformance.

EXAMPLE 2

[0090] A raw material polymer solution was prepared in the same manneras in Example 1, with the exception of using 4 wt % of polyvinylpyrrolidone and 78 wt % of N,N-dimethyl acetoamide. The mixture ratio ofpolyvinyl pyrrolidone to polysulfone in the raw material polymersolution was 22.2 wt %. The performance of this membrane is shown inTable 1.

[0091] This membrane not only allows elution only in a very smallamount, but also permits adhesion of blood proteins and blood plateletonly to a limited extent. In addition, the membrane was found to excelin dialysis performance based on the fact that the membrane exhibits alow albumin permeability and excels in P₂-microglobulin clearance.

EXAMPLE 3

[0092] A raw material polymer solution was prepared in the same manneras in Example 1, with the exception of using 4.8 wt % of polyvinylpyrrolidone and 77.2 wt % of N,N-dimethyl acetoamide. The mixture ratioof polyvinyl pyrrolidone to polysulfone in the raw material polymersolution was 26.7 wt %. The performance of this membrane is shown inTable 1.

[0093] This membrane not only allows elution only in a very smallamount, but also permits adhesion of blood proteins and blood plateletonly in a small amount. In addition, the membrane was found to excel indialysis performance based on the fact that the membrane exhibits lowalbumin permeability and excels in β₂-microglobulin clearance.

EXAMPLE 4

[0094] The same experiment as in Example 3 was conducted except forusing a mixed solution of 52 wt % of N,N-dimethyl acetoamide and 48% ofwater as an inner liquid. The performance of this membrane is shown inTable 1.

[0095] This membrane not only allows elution only in a very smallamount, but also permits adhesion of blood proteins and blood plateletonly in a small amount. In addition, the membrane was found to excel indialysis performance based on the fact that the membrane exhibits lowalbumin permeability and excels in β₂-microglobulin clearance.

COMPARATIVE EXAMPLE 1

[0096] With the exception of not using γ-ray irradiation, a membrane wasprepared in the same manner as in Example 1. The results are shown inTable 2. The membrane elution test solution was found to exhibitabsorbance of more than 0.04 due to elution of PVP.

COMPARATIVE EXAMPLE 2

[0097] A raw material polymer solution was prepared in the same manneras in Example 1, with the exception of using 5.0 wt % of polyvinylpyrrolidone and 77.0 wt % of N,N-dimethyl acetoamide. The mixture ratioof polyvinyl pyrrolidone to polysulfone in the raw material polymersolution was 27.8 wt %. The performance of this membrane is shown inTable 2.

COMPARATIVE EXAMPLE 3

[0098] A raw material polymer solution was prepared in the same manneras in Example 1, with the exception of using 3.6 wt % of polyvinylpyrrolidone and 78.4 wt % of N,N-dimethyl acetoamide. The mixture ratioof polyvinyl pyrrolidone to polysulfone in the raw material polymersolution was 20.0 wt %.

[0099] The performance of this membrane is shown in Table 2.

COMPARATIVE EXAMPLE 4

[0100] The same experiment as in Example 3 was conducted except forusing a mixed solution of 60 wt % of N,N-dimethyl acetoamide and 40% ofwater as an inner liquid. The performance of this membrane is shown inTable 2. TABLE 1 Example 1 Example 2 Example 3 Example 4 Internaldiameter of 195 201 190 193 membrane (μm) External diameter of 280 288282 284 membrane (μm) Water permeability (mL/(m² · hr · mmHg)) 20 18 25390 Permeability of not more not more not more 0.25 Albumin (%) than0.01 than 0.01 than 0.01 Permeability of PVP (%) 4 4 5 72 Concentrationof PVP on 35 30 44 36 the inner surface of the membrane (wt %) Presenceof water yes yes yes yes insoluble PVP Absorbance of elusion 0.022 0.0200.035 0.023 test solution Presence of membrane no no no no pore holdingagent in elution test solution Amount of platelet 15.5 17.5 4.2 13.8adhesion (LDH-Unit/m²) Amount of plasma 2.1 5.5 1.8 2.0 protein solutionabsorption (mg/g) Water permeability of 190 170 260 3,100 wet membranebefore drying (mL/ (m² · hr · mmHg)) Permeability of Albumin 0.32 0.340.35 0.51 in wet membrane before drying (%) Permeability of PVP 77 84 8499 in wet membrane before drying (%)

[0101] TABLE 2 ComparativeExample 1 2 3 4 5 6 Internal diameter of 195200 199 196 200 191 membrane (μm) External diameter of 290 298 290 297291 276 membrane (μm) Water permeability 20 35 15 970 8 15 (mL/(m² ·hrmmHg)) Permeability of Albumin (%) not more not more not more 0.37 notmore not more than 0.01 than 0.01 than 0.01 than 0.01 than 0.01Permeability of PVP (%) 4 5 4 79 0 4 Concentration of PVP on the 35 4728 33 34 36 inner surface of the membrane (wt %) Presence of waterinsoluble no yes yes yes yes yes PVP Absorbance of elusion test 0.0440.040 0.018 0.021 0.020 0.021 solution Presence of membrane pore no nono no no no holding agent in elution test solution Amount of plateletadhesion 15.5 3.8 19.6 15.0 15.1 16.8 (LDH-Unit/m²) Amount of plasmaprotein 2.1 1.1 5.9 2.8 2.1 3.0 solution absorption (mg/g) Waterpermeability of wet membrane before drying 190 310 130 8,600 76 190(mL(m² · hrmmHg)) Permeability of Albumin in wet membrane before drying0.32 0.38 0.31 0.62 0.18 0.32 (%) Permeability of PVP in wet 77 85 76100 52 77 membrane before drying (%)

INDUSTRIAL APPLICABILITY

[0102] The membrane of the present invention has excellent dialysisperformance and allows very little elution from the membrane and littleadhesion of blood proteins and platelets and can be used in medicines,medical treatment, and general industrial use.

1. (cancelled)
 2. A hollow fiber blood purification membrane allowinglittle elution, which is a dry membrane containing no membrane poreholding agent, prepared by providing a wet membrane made from a materialcomprising polysulfone-based polymer and polyvinyl pyrrolidone, whichdoes not contain a membrane pore holding agent and has a pure waterpermeability of not less than 100 mL/(m²·hr·mmHg), permeability ofpolyvinyl pyrrolidone with a weight average molecular weight of 40,000of more than 75%, and permeability of albumin in bovine blood plasma ofnot less than 0.3%, and drying the wet membrane at a temperature of notmore than 120° C. after removing the solvent to constrict the pore size,the dry membrane: (a) having a sponge-like structure with the pore sizecontinuously decreasing from the outer surface of the membrane towardthe compact layer of the inner surface, (b) having pure waterpermeability of 10-1,000 mL/(m²·hr·mmHg), (c) having polyvinylpyrrolidone (weight average molecular weight of 40,000) permeability ofnot more than 75%, (d) having permeability of albumin in bovine bloodplasma of less than 0.3%, (e) having an absorbance in a membrane elutiontest solution of less than 0.04 and not containing a membrane poreholding agent in the elution test solution, and (f) comprising apolysulfone-based polymer and polyvinyl pyrrolidone, with a polyvinylpyrrolidone content of 30-45 wt % on the inner surface of the membrane.3. The blood purification membrane according to claim 2, containingpolyvinyl pyrrolidone insoluble in water.
 4. (cancelled)
 5. The methodfor preparing the hollow fiber blood purification membrane, wherein themethod comprises providing a wet membrane made from a materialcomprising polysulfone-based polymer and polyvinyl pyrrolidone, whichdoes not contain a membrane pore holding agent and has a pure waterpermeability of 100 mL/(m²·hr·mmHg), permeability of polyvinylpyrrolidone with a weight average molecular weight of 40,000 of morethan 75%, and permeability of albumin in bovine blood plasma of not lessthan 0.3%, and drying the wet membrane at a temperature of not more than120° C. after removing the solvent to constrict the pore size, and thedry membrane: (a) having a sponge-like structure with the pore sizecontinuously decreasing from the outer surface of the membrane towardthe compact layer of the inner surface, (b) having a pure waterpermeability of 10-1,000 mL/(m²·hr·mmHg), (c) having a polyvinylpyrrolidone (weight average molecular weight of 40,000) permeability ofnot more than 75%, (d) having permeability of albumin in bovine bloodplasma of less than 0.3%, (e) having an absorbance in a membrane elutionsolution test solution of less than 0.04 and not containing a membranepore holding agent in the elution test solution, and (f) comprising apolysulfone-based polymer and polyvinyl pyrrolidone, with a polyvinylpyrrolidone content of 30-45 wt % on the inner surface of the membrane.6. The method for preparing the wet membrane according to claim 5,comprising injecting a raw material polymer solution and an inner liquidfrom double-ring nozzles, causing the injected material to pass throughan air gap, and causing the material to coagulate in a coagulation bath,thereby producing a hollow fiber membrane, wherein the ratio of the airgap to the spinning speed is 0.01-0.1 m/(m/min).
 7. The method accordingto claim 6, wherein the raw material polymer solution comprises apolysulfone-based polymer, polyvinyl pyrrolidone and solvent, with theratio of polyvinyl pyrrolidone to the polysulfone-based polymer being18-27 wt %.
 8. The method according to claim 5, wherein the membrane isirradiated with radiation after drying.
 9. The method according to claim6, wherein the membrane is irradiated with radiation after drying. 10.The method according to claim 7, wherein the membrane is irradiated withradiation after drying.